Effect of metformin treatment on multiple cardiovascular disease risk factors in patients with type 2 diabetes mellitus

In light of the conflicting results of the recent United Kingdom Prospective Study (UKPDS), where diabetic patients on metformin monotherapy had lower all-cause mortality and the addition of metformin in sulfonylurea-treated patients was associated with an increased risk of diabetes-related death, we sought to compare the effects on cardiovascular disease (CVD) risk factors of metformin monotherapy with metformin treatment when added to a sulfonylurea compound in patients with type 2 diabetes. Thirty-one volunteers with type 2 diabetes mellitus, 16 on dietary therapy and 15 on sulfonylurea monotherapy (SU), were treated with metformin for 12 weeks. Measurements were made of (1) fasting plasma glucose, hemoglobin A(1c) (HbA(1c)), lipid, remnant lipoprotein cholesterol (RLP-C) levels, and low-density lipoprotein (LDL) particle size; (2) daylong plasma glucose, insulin, free fatty acid (FFA), triglyceride (TG), and RLP-C concentrations; and (3) fasting levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and soluble E-selectin (sE-selectin). Fasting plasma glucose concentrations decreased to a similar degree after treatment with metformin in both the metformin monotherapy group (12.45 +/- 0.48 v 9.46 +/- 0.47 mmol/L, P <.001) and the combined SU and metformin therapy group (14.09 +/- 0.51 v 10.57 +/- 0.85 mmol/L, P =.001). Fasting plasma lipid concentrations and LDL particle size did not significantly change in either treatment group, whereas fasting RLP-C concentrations were significantly lower in the metformin monotherapy group (0.43 +/- 0.09 v 0.34 +/- 0.07 mmol/L, P =.02). Daylong concentrations of plasma glucose, FFA, TG, and RLP-C were lower to a similar degree in both treatment groups, whereas daylong plasma insulin concentrations were unchanged. Fasting plasma sVCAM-1 levels were significantly lower in both the metformin monotherapy group (484 +/- 19 v 446 +/- 18 ng/mL, P =.02) and the combined SU and metformin therapy group (496 +/- 29 v 456 +/- 31 ng/mL, P =.05), whereas fasting plasma sICAM-1 and sE-selectin levels were essentially unchanged. Administration of metformin, either as monotherapy or in combination with a sulfonylurea drug, improved glycemic control and led to a decrease in several CVD risk factors in patients with type 2 diabetes.     

Mechanisms of high-density lipoprotein cholesterol effects on the endothelial function in hyperlipemia

High-density lipoprotein-cholesterol (HDL-c) has a favorable influence on the endothelial function, but the mechanisms of this protective action are not fully understood. We studied lipid parameters, soluble adhesion molecules (vascular cell adhesion molecule-1 [VCAM-1], intercellular adhesion molecule [ICAM-1], E-selectin) oxidized low-density lipoproteins (LDL), and brachial-artery flow-mediated vasodilation (FMV) in 184 hyperlipemic patients (90 men, age 54 +/- 10 years, waist/hip circumference ratio 0.89 +/- 0.07, LDL-cholesterol [LDL-c] 4.9 +/- 1.3 mmol/L, triglycerides 1.8 +/- 0.9 mmol/L, HDL-c 1.3 +/- 0.5 mmol/L) after excluding those with current smoking, diabetes, hypertension, and vascular diseases. Patients were divided into 2 groups on the basis of HDL-c levels: < 1.03 mmol/L (n = 53) v >or= 1.03 mmol/L (n = 131). Patients with low HDL-c showed significantly lower LDL-c (P <.05), higher triglycerides (P <.001), higher body mass index (P <.02), lower FMV (3.7% +/- 2.0% v 4.9% +/- 3.4%, P <.002), higher VCAM-1 (1,195 +/- 395 ng/mL v 984 +/- 303 ng/mL, P <.01), and higher ICAM-1 (406 +/- 78 ng/mL v 364 +/- 68 ng/mL, P <.01). E-selectin and oxidized LDL showed no significant differences. In a multivariate age, oxidized LDL and brachial artery diameter predicted a lower FMV, while HDL-c was an independent predictor of a greater FMV (P =.003). Increasing levels of VCAM-1 and ICAM-1 were predicted by lower HDL-c, while higher oxidized LDL predicted higher VCAM-1 (P <.05). Our data suggest that in hyperlipemic subjects free of cardiovascular disease low HDL-c negatively modulates endothelial function through a lack of oxidation inhibition and a concomitant overexpression of adhesion molecules.     

可溶性血管细胞黏附分子-1与2型糖尿病及其并发症的相关性研究

目的探讨血清可溶性血管细胞黏附分子-1(sVCAM-1)与2型糖尿病及其并发症的关系.方法采用酶联免疫吸附法测定61例合并高血压和微血管并发症的糖尿病患者及36例正常人血清中sVCAM-1水平.结果2型糖尿病患者的sVCAM-1水平[(973.25±73.38)μg/L]明显高于非糖尿病患者[(230.45±12.47)μg/L],P＜0.001.合并高血压患者sVCAM-1[(1263.99±87.00)μg/L]较微血管病变者[(726.57±95.40)μg/L]增高更明显(P＜0.001).结论sVCAM-1参与了糖尿病血管并发症的发生和发展.     

Signs of maternal vascular dysfunction precede preeclampsia in women with type 1 diabetes

AIM: This study aims to test the hypothesis that vascular dysfunction is present early in pregnancy in women with type 1 diabetes who subsequently develop preeclampsia. METHODS: Eighty-three women with type 1 diabetes of more than 10 years duration were followed up prospectively during pregnancy. External ultrasound was used to measure the dilatory response of the brachial artery to postischemic increased blood flow (endothelium-dependent, flow-associated dilatation) and to nitroglycerin (NTG) [endothelium-independent, NTG-induced dilatation (NID)] at Gestational Weeks 11 and 29. Plasma concentrations of the vascular markers vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin, and von Willebrand factor antigen were also measured together with 24-h urinary albumin excretion (UAE), blood pressure (BP), and HbA(1C). RESULTS: Fourteen (17%) of the 83 women developed preeclampsia. NID was significantly impaired at Week 29 in women prone to preeclampsia (108.8+/-7.0% vs. 116.8+/-8.9%, mean+/-S.D., P<.05), and the plasma concentrations of VCAM-1 and ICAM-1 were significantly elevated at Gestational Week 11 (612+/-82 vs. 516+/-109 microg/l, P<.005 and 293+/-67 vs. 255+/-57 microg/l, P<.05, respectively). Women who later developed preeclampsia were also characterized by higher UAE, higher BP, and higher HbA(1C) than women who did not [Gestational Week 11: 194 (3-1104) vs. 7 (0-412) mg/24 h, median (range), P=.0003; 122+/-12/75+/-6 vs. 111+/-11/69+/-9 mmHg, mean+/-S.D., P<.01; and 8.2% (5.9-10.5%) vs. 7.2% (5.3-10.9%), P=.008, respectively]. CONCLUSION: This prospective study indicates that signs of maternal vascular dysfunction precede development of preeclampsia in women with type 1 diabetes.     

2型糖尿病患者糖耐量正常一级亲属血管内皮功能及炎症因子的研究

目的研究2型糖尿病患者一级亲属糖耐量正常者(FDR)的血管内皮功能、炎症因子水平及其影响因素。方法测定31例正常人、57例FDR的血管内皮功能、血浆纤溶酶原激活物抑制物1(PAI1)及血清可溶性血管细胞黏附分子1(VCAM1)水平,同时测定胰岛素水平,计算胰岛素敏感性(IAI)。结果与正常对照组比较,FDR内皮依赖性血管舒张功能减低[(1245±337)%比(503±034)%],IAI降低[(-379±057)比(-411±046)],血浆PAI1水平升高[(3046±1228)μg/L比(3925±654)μg/L],血清VCAM1水平升高[(63731±10732)μg/L比(74239±12431)μg/L],差异均有统计学意义(P值均<005)。结论糖耐量正常的2型糖尿病患者一级亲属胰岛素敏感指数下降、血管内皮功能受损、纤溶活性降低,且血管内皮功能失调与胰岛素抵抗密切相关。     

Increased insulin sensitivity and decreased insulin secretion in offspring of insulin-sensitive type 2 diabetic patients

To investigate the early defects of glucose metabolism in insulin-sensitive type 2 diabetes, we performed oral and frequently sampled intravenous glucose tolerance tests (OGTT and FSIGT) with minimal model analysis in 15 offspring of Japanese type 2 diabetics with normal insulin sensitivity (insulin resistance index of homeostasis model assessment [HOMA-R] < 2.0) and in 20 healthy control subjects without a family history of type 2 diabetes. The frequency of impaired glucose tolerance (IGT) was 40% (6 of 15) in the offspring and 0% (0 of 20) in the controls. Fasting plasma glucose (4.8 +/- 0.1 v4.6 +/- 0.1 mmol/L, P = .18) and immunoreactive insulin ([IRI] 29.9 +/- 2.5 v 28.3 +/- 2.5 pmol/L, P = .64) were comparable between the offspring and the controls. The rate of glucose disappearance (KG) was significantly lower in the offspring versus the control group (2.00 +/- 0.22 v 2.60 +/- 0.17 min(-1), P= .03). The insulin sensitivity index (Si) was significantly greater in the offspring versus the controls (2.68 +/- 0.41 v 1.71 +/- 0.17 x 10(-4) min(-1) x pmol/L , P = .02). First-phase insulin secretion (FPI) to intravenous glucose was significantly lower in the offspring versus the control group (886 +/- 110 v 2,296 +/- 267 min x pmol/L, P< .01). Glucose effectiveness (SG) was comparable between the offspring and control groups. The disposition index (Si x FPI) was significantly lower in the offspring versus the controls (2,106 +/- 256 v 3,652 +/- 490 x 10(-4), P = .02). When the offspring were subdivided into 2 groups by glucose tolerance status, both normal glucose tolerance (NGT) offspring and IGT offspring showed a significant decrease in FPI and increase in Si. Thus, although the offspring of insulin-sensitive type 2 diabetics had increased insulin sensitivity, the impairment in insulin secretion was more dominant. Our results suggest that the early metabolic abnormality in insulin-sensitive type 2 diabetes is an insulin secretory dysfunction despite increased insulin sensitivity.     

Effect of improving glycemic control on low-density lipoprotein particle size in type 2 diabetes

The current study sought to assess the effect of improving glycemic control in type 2 diabetes on the components of diabetic dyslipidemia, especially low-density lipoprotein (LDL) size. A total of 33 type 2 diabetic patients (48.5% women, age 59.6 +/- 11.1 years, body mass index [BMI] 28.9 +/- 4.9, diabetes duration 6 [0 to 40] years, 40.7% on insulin) were seen at the hospital because of poor glycemic control (hemoglobin A(1c) [HbA(1c)] 10.33% +/- 1.89%). Triglyceride, LDL-cholesterol (LDLc, Friedewald/ ultracentrifugation), high-density lipoprotein HDL-cholesterol (HDLc, direct method), apolipoproteins AI (apoAI) and B (apoB) (immunoturbidimetry), and LDL size (gradient gel electrophoresis) were measured at baseline and after improvement in glycemic control (decrease >/= 1 percentage point in HbA(1c) and final HbA(1c) 相似文献   

High serum concentrations of soluble E-selectin correlate with obesity but not fat distribution in patients with type 2 diabetes mellitus

Serum concentrations of soluble adhesion molecules, eg, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin are elevated in patients with type 2 diabetes. However, little is known about the role of obesity or abnormal fat distribution in inducing upregulation of adhesion molecules. To investigate this issue, soluble ICAM-1, VCAM-1, and E-selectin levels were evaluated in 40 obese and 30 nonobese patients with type 2 diabetes. Both groups were matched for age, sex, and glycosylated hemoglobin (HbA(1c)) levels. Computed tomography (CT) was used to measure the abdominal subcutaneous and visceral fat areas. Soluble ICAM-1 and VCAM-1 levels did not differ significantly between obese and nonobese patients. However, serum concentrations of soluble E-selectin were significantly higher in obese than in nonobese patients (90 +/- 7 v 56 +/- 4 ng/mL, P <.01). Soluble E-selectin levels significantly correlated with body mass index, subcutaneous fat area, and visceral fat area (Rho = 0.48, 0.37, and 0.30, respectively). Stepwise multiple regression analysis showed that body mass index (F = 16.7), but not subcutaneous and visceral fat areas (F = 0.29 and 0.01, respectively), significantly and independently correlated with soluble E-selectin levels. Our results suggest that obesity may induce endothelial activation or increased shedding of cell surface E-selectin that leads to subsequent increase in soluble E-selectin levels. The high serum concentrations of E-selectin closely correlated with increased total fat volume, but not with regional fat distribution.     

Postprandial lipidemia is normal in non-obese type 2 diabetic patients with relatively preserved insulin secretion

To assess postprandial lipidemia in normotriglyceridaemic type 2 diabetic patients treated with diet only, 12 non-obese patients (8 males, hemoglobin A(1c) [HbA(1c)] 6.80 +/- 0.67%) and 14 controls of similar age, body mass index (BMI), and fasting triglyceride (Tg) were given a test meal (58 g fat, 100,000 IU vitamin A). Fasting low-density lipoprotein (LDL) cholesterol (LDLc), high-density lipoprotein (HDL) cholesterol (HDLc), free fatty acids, and apolipoprotein B (apoB), and fasting and postprandial Tg, retinylpalmitate (RP), LDL size, glucose, and insulin were measured. The homeostasis assessment model (HOMA) index and lipoprotein (Lpl) and hepatic (HL) lipase activities were estimated. Patients showed lower fasting HDLc (1.12 +/- 0.26 v 1.40 +/- 0.28 mmol/L, P =.02) and a trend towards smaller LDL particles, which was significant 4 hours postprandially (25.86 +/- 0.40 v 26.16 +/- 0.30 nm, P =.04). The area under the curve of Tg (AUC-Tg) and RP, and Lpl were similar, but HL was higher in patients (156.63 +/- 23.89 v 118 +/- 43.27 U/L, P =.011). HL correlated inversely with LDL size and directly with the HOMA index. In conclusion, normotriglyceridemic type 2 diabetic patients with insulin resistance but relatively preserved insulin secretion show low fasting HDLc and increased HL, but normal postprandial lipidemia.     

Longitudinal changes in risk variables of insulin resistance syndrome from childhood to young adulthood in offspring of parents with type 2 diabetes: the Bogalusa Heart Study

The occurrence of metabolic abnormalities related to insulin resistance syndrome in nondiabetic offspring of type 2 diabetic parents is known. However, information is lacking on the timing and the course of development of the components of this syndrome from childhood to adulthood in the offspring of parents with diabetes. This aspect was examined in a community-based cohort with (n = 303) and without (n = 1,136) a parental history of type 2 diabetes followed longitudinally since childhood (ages 4 to 17 years; mean follow-up period, 15 years) by repeated surveys. Offspring with parental diabetes versus those without such history had significantly excess generalized and truncal adiposity as measured by body mass index (BMI) and subscapular skinfold beginning in childhood, higher levels of fasting insulin and glucose and homeostasis model assessment index of insulin resistance (HOMA-IR) from adolescence, and higher levels of low-density lipoprotein (LDL) cholesterol and triglycerides and lower levels of high-density lipoprotein (HDL) cholesterol in adulthood. Many of these risk variables changed adversely at an increased rate in offspring of diabetic parents. In a multivariate analysis, parental diabetes was an independent predictor of longitudinal changes in adiposity, glucose, insulin, HOM-IR, systolic and diastolic blood pressure, and LDL cholesterol in the offspring, regardless of race and gender. As young adults, the offspring of diabetic parents had a higher prevalence of generalized (BMI > 30, 36% v 16%, P =.0001) and visceral (waist > 100 cm, 15% v 6%, P =.0001) obesity, hyperinsulinemia indicative of insulin resistance (insulin > 18 microU/mL, 15% v 8%, P =.0001), hyperglycemia (>or=110 mg/dL, 2% v 0.5%, P =.02), high LDL cholesterol (>or=160 mg/dL, 11% v 7%, P =.02), low HDL cholesterol (<40 mg/dL for males and <50 mg/dL for females, 40% v 31%, P =.004), high triglycerides (>or=150 mg/dL, 23% v 15%, P =.0001), and hypertension (>140/90 mm Hg, 11% v 6%, P =.004). Thus, the offspring of diabetic parents displayed excess body fatness beginning in childhood and accelerated progression of adverse risk profile characteristics of insulin resistance syndrome from childhood to young adulthood. These observations have important implications for early prevention and intervention.     

Effect of physical exercise on lipoprotein(a) and low-density lipoprotein modifications in type 1 and type 2 diabetic patients

To evaluate the effect of physical exercise on blood pressure, the lipid profile, lipoprotein(a) (Lp(a)), and low-density lipoprotein (LDL) modifications in untrained diabetics, 27 diabetic patients (14 type 1 and 13 type 2) under acceptable and stable glycemic control were studied before and after a supervised 3-month physical exercise program. Anthropometric parameters, insulin requirements, blood pressure, the lipid profile, Lp(a), LDL composition, size, and susceptibility to oxidation, and the proportion of electronegative LDL (LDL(-)) were measured. After 3 months of physical exercise, physical fitness improved (maximal O2 consumption [VO2max], 29.6 +/- 6.8 v 33.0 +/- 8.4 mL/kg/min, P < .01). The body mass index (BMI) did not change, but the waist circumference (83.2 +/- 11.8 to 81.4 +/- 11.2 cm, P < .05) decreased significantly. An increase in the subscapular to triceps skinfold ratio (0.91 +/- 0.37 v 1.12 +/- 0.47 cm, P < .01) and midarm muscle circumference ([MMC], 23.1 +/- 3.4 v 24.4 +/- 3.7 cm, P < .001) were observed after exercise. Insulin requirements (0.40 +/- 0.18 v 0.31 +/- 0.19 U/kg/d, P < .05) and diastolic blood pressure (80.2 +/- 10 v 73.8 +/- 5 mm Hg, P < .01) decreased in type 2 diabetic patients. High-density lipoprotein cholesterol (HDL-C) increased in type 1 patients (1.48 +/- 0.45 v1.66 +/- 0.6 mmol/L, P < .05), while LDL cholesterol (LDL-C) decreased in type 2 patients (3.6 +/- 1.0 v3.4 +/- 0.9 mmol/L, P < .01). Although Lp(a) levels did not vary in the whole group, a significant decrease was noted in patients with baseline Lp(a) above 300 mg/L (mean decrease, -13%). A relationship between baseline Lp(a) and the change in Lp(a) (r = -.718, P < .0001) was also observed. After the exercise program, 3 of 4 patients with LDL phenotype B changed to LDL phenotype A, and the proportion of LDL(-) tended to decrease (16.5% +/- 7.4% v 14.0% +/- 5.1%, P = .06). No changes were observed for LDL composition or susceptibility to oxidation. In addition to its known beneficial effects on the classic cardiovascular risk factors, regular physical exercise may reduce the risk of cardiovascular disease in diabetic patients by reducing Lp(a) levels in those with elevated Lp(a) and producing favorable qualitative LDL modifications.     

Circulating E-selectin,vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 in men with coronary artery disease assessed by angiography and disturbances of carbohydrate metabolism

It is hypothesized that adhesion molecules could be an early predictor of coronary artery disease. Therefore we investigated the relationship between the concentrations of soluble forms of adhesion molecules and disturbances of glucose metabolism in 78 men referred for coronary angiography but with no previous history of diabetes. The group consisted of 78 men (mean age, 47.6 +/- 7.0 years; mean body mass index [BMI], 28.4 +/- 3.24 with the symptoms of angina pectoris and positive exercise test. All subjects were given a standard oral glucose tolerance test (OGTT) with glucose and insulin estimations. Fasting plasma concentrations of the soluble (s) forms of E-selectin, intercellular adhesion cell molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and HbA(1c) were also measured. According to the OGTT, 10.2% of the patients (n = 8) fulfilled the criteria for type 2 diabetes mellitus and 44.9% (n = 35) for impaired glucose tolerance (IGT). The highest concentrations of sE-selectin were observed in patients with type 2 diabetes mellitus and were significantly higher in comparison to the group with normal glucose tolerance and IGT. The concentration of sVCAM-1 increased with the progression of disturbances of glucose metabolism and remained the highest in type 2 diabetic patients. sICAM-1 concentration was not significantly different. sE-selectin concentration correlated significantly with fasting glucose (r = 0.23, P =.041), postload glucose (r = 0.39, P =.001), and postload insulin (r = 0.28, P =.023). sVCAM-1 was significantly related to the postload glucose concentration (r = 0.30, P =.009). A significant correlation between sICAM-1 concentration and postload insulin was also observed (r = 0.27, P =.025). This would suggest that hyperglycemia increases sE-selectin and sVCAM-1 in plasma, which reflects excessive formation of atherosclerotic plaques in patients with disturbances of glucose metabolism.     

Role of angiotensin II type 1 receptor in the regulation of cellular adhesion molecules in atherosclerosis

BACKGROUND: Inflammation is a central feature of coronary artery disease (CAD) that is characterized by increased expression of cellular adhesion molecules with the exception of L-selectin. L-selectin is a leukocyte adhesion molecule that is rapidly shed after leukocyte activation so that it appears to be decreased in CAD. The renin-angiotensin system (RAS) is implicated in atherogenesis and up-regulates these molecules. OBJECTIVES: The aim of this study was to investigate the effect of angiotensin type 1 (AT1) receptor antagonism on serum and leukocyte adhesion molecule expression in patients with CAD. Blood samples were collected from 31 patients before and after 8 weeks of treatment with losartan (44 +/- 2 mg/d, mean +/- SE), an AT1 receptor antagonist. We measured serum intercellular adhesion molecule-1, vascular cell adhesion molecule-1, endothelial-leukocyte adhesion molecule, and C-reactive protein (CRP). By flow cytometry, we also measured the expression of leukocyte CD11a, CD11b, CD11c, CD18, CD31, CD49d, and CD62L (L-selectin) in 13 patients. RESULTS: Treatment with losartan decreased systolic blood pressure (141 +/- 3 vs 135 +/- 4 mm Hg, P =.04) and increased plasma renin activity (1.2 +/- 0.4 vs 2.7 +/- 0.5 ng/mL/h, P =.001). There was a significant increase in L-selectin expression on monocytes (86 +/- 6 vs 118 +/- 10 MESF units, P =.007), lymphocytes (52 +/- 10 vs 79 +/- 8, P =.01), and granulocytes (124 +/- 7 vs 156 +/- 18, P =.056). However, there were no changes in the other leukocyte and serum adhesion molecules or CRP. CONCLUSIONS: These findings suggest that AT1 receptor antagonism selectively modulates L-selectin expression on leukocytes and that endogenous stimulation of AT1 receptors by the RAS contributes to the activation of leukocytes and decreased expression of L-selectin in CAD.     

Altered lipid profile, leptin, insulin, and anthropometry in offspring of South Asian immigrants in the United States

South Asians who immigrate to the United States have a propensity toward insulin resistance, central obesity, and elevated total cholesterol:high-density lipoprotein (HDL) ratio. To evaluate whether these alterations are apparent at a younger age, we studied 32 offspring of South Asian immigrants and compared them with 29 of European descent between 18 to 30 years of age. American-born South Asian males had significantly higher total cholesterol, low-density lipoprotein (TC:LDL) ratios, triglycerides, and fasting insulin levels (13.9 +/- 7.1 and 10.0 +/- 5.5 microU/mL, P <.01) than their European counterparts. The South Asian females only had increased plasma insulin levels (15.3 +/- 8.8 and 10.0 +/- 5.1 microU/mL, P =.05). The entire South Asian group had higher truncal skinfold thickness (40.1 +/- 18.1 and 30.3 +/- 12.6 mm, P = <.05) and lower insulin-like growth factor binding protein (IGFBP)-1 levels (46.8 +/- 33.4 and 56.0 +/- 33.4 microg/L, P =.05). Plasma leptin levels were also significantly higher in both males (4.3 +/- 2.5 v 2.8 +/- 1.3 ng/mL, P =.0001) and females (20.5 +/- 10.3 v 10.3 +/- 6.3 ng/mL, P =.002) South Asian subjects. A significant correlation between plasma leptin and insulin, triglycerides, TC, and body mass index (BMI) was seen in the South Asian males. South Asians born in the United States show evidence for an altered metabolic profile in young adulthood. The relative contributions of inheritance and nutritional practices early in life to this alteration remain unclear.     

Effects of rosiglitazone on endothelial function in men with coronary artery disease without diabetes mellitus

Recent data have shown that peroxisome proliferator-activated receptor-gamma agonists may exert protective effects on the vascular endothelium by amelioration of insulin resistance and through direct anti-inflammatory effects. In this study we assessed the effect of rosiglitazone on biochemical and biophysical indexes of endothelial function in male, nondiabetic patients with coronary artery disease. Consecutive male subjects (n = 71) with clinically stable, angiographically documented coronary artery disease and without diabetes mellitus were investigated. Patients were randomized in a double-blind manner to placebo or rosiglitazone for a total of 24 weeks. Flow-mediated dilation (FMD) of the brachial artery, C-reactive protein, von Willebrand factor, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 levels, and parameters of glucose and lipid metabolism were measured at baseline and after 12 and 24 weeks of treatment. Rosiglitazone treatment significantly reduced C-reactive protein (median 0.56 mg/L [interquartile range 0.33 to 1.02] to 0.33 mg/L [interquartile range 0.26 to 0.40], p <0.01), von Willebrand factor (139 +/- 47 to 132 +/- 44 IU/dl, p = 0.02), insulin resistance index (p = 0.05), and mean low-density lipoprotein (LDL) density (p <0.001) compared with placebo. However, no significant differences were seen between the rosiglitazone and placebo groups with regard to brachial artery FMD, intercellular adhesion molecule-1, or vascular cell adhesion molecule-1 levels. Rosiglitazone treatment significantly increased LDL (2.62 +/- 0.72 to 2.95 +/- 0.84 mmol/L, p = 0.03) and triglyceride (1.23 +/- 0.63 to 1.56 +/- 0.98 mmol/L, p = 0.04) levels. Thus, rosiglitazone reduced markers of inflammation and endothelial activation, but this did not translate into an improvement in FMD. Increased LDL and triglyceride levels may have played a role.     

Soluble adhesion molecules, endothelial function and vitamin E in type 1 diabetes

BACKGROUND: Elevated levels of soluble adhesion molecules are found in subjects with vascular disease and inconsistently in subjects with conditions predisposing them to atherosclerosis, such as hypercholesterolaemia and diabetes. Oxidized low-density lipoprotein (LDL), protein kinase C and lower than normal levels of NO appear to be important for expression of adhesion molecules, raising the possibility that vitamin E is useful for downregulating levels. We have recently shown that administration of 1000 IU vitamin E for 3 months will improve endothelial vasodilator function (EVF) in uncomplicated type-1 diabetes. OBJECTIVE: To determine whether levels of soluble adhesion molecules in young subjects with uncomplicated diabetes are elevated, whether there is a relationship between levels of soluble adhesion molecule and EVF as well as parameters of diabetes and lipid levels and whether an improvement in EVF related to vitamin E therapy is also associated with a decrease in levels of soluble adhesion molecules. DESIGN: A randomized, placebo-controlled, study. RESULTS: There was no difference between levels of soluble vascular cell adhesion molecule-1 (VCAM-1; 621 +/- 17 versus 635 +/- 37 ng/ml) and P-selectin (59 +/- 2 versus 57 +/- 6 ng/ml) for the diabetic and control groups. For the diabetic cohort, levels of soluble VCAM-1 were inversely related to flow-mediated vasodilatation of the brachial artery (r = -0.41, P < 0.005) and directly related to levels of total cholesterol (r = 0.44, P < 0.005) and LDL cholesterol (r = 0.42, P < 0.01) and duration of diabetes (r = 0.55, P < 0.0005) but there was no relationship with susceptibility of LDL to oxidation or vitamin-E content of LDL. Levels of soluble P-selectin were directly related to duration of diabetes (r = 0.43, P < 0.05) and inversely related to size of LDL particles (r = 0.32, P < 0.05) but were not related to EVF. Vitamin E produced no change in levels of soluble P-selectin and VCAM-1. CONCLUSIONS: Levels of soluble VCAM-1 and P-selectin in young subjects with type-1 diabetes and no evidence of overt vascular disease do not appear to be elevated and are not influenced by vitamin-E supplementation.     

Initiation of insulin therapy reduces serum concentrations of high-sensitivity C-reactive protein in patients with type 2 diabetes

Atherosclerosis has highly important chronic inflammatory aspects. We investigated anti-inflammatory effects upon initiating insulin therapy by measuring serum high-sensitivity C-reactive protein (hsCRP) and plasma fibrinogen and serum monocyte chemoattractant protein (MCP)-1in patients with poorly controlled type 2 diabetes. In 18 inpatients with type 2 diabetes, we measured serum hsCRP, plasma fibrinogen, serum MCP-1, body weight (BW), girth, and fasting plasma glucose (FPG) before and 2 weeks (14.0 +/- 2.5 days) after initiation of insulin therapy. Daily insulin doses (in units) were approximately 0.2 x BW (in kilograms). Various changes (ratio) were calculated as the ratio of the value during treatment to the pretreatment value. Significant decreases occurred for log(10) hsCRP and FPG (-0.025 +/- 0.557 mg/L, 215 +/- 64.3 mg/dL v -0.213 +/- 0.571 mg/L, 129.8 +/- 32.1 mg/dL; P =.0121, and P =.00002, respectively). This was particularly true for log(10) hsCRP in patients whose BW was unchanged or increased between measurement (P =.0050). There were no significant differences between pretreatment and treatment values for fibrinogen and MCP-1. However, MCP-1 decreased significantly in the group with high-value in the first time point (MCP-1 > 250 pg/mL, n = 9; P =.0224) compared with the low-value group (MCP-1 < 250 pg/mL, n = 9; P =.3164). No significant correlation was found between hsCRP ratio and fibrinogen ratio, MCP-1 ratio, BW ratio, waist girth ratio, or FPG ratio. In conclusion, newly initiated insulin therapy in patients with poorly controlled type 2 diabetes decreased serum hsCRP. The decrease in hsCRP may have resulted largely from anti-inflammatory effects of insulin.     

F2 isoprostane is already increased at the onset of type 1 diabetes mellitus: effect of glycemic control

Much evidence has suggested that oxidative stress (OS) may play a role in the pathogenesis of diabetic complications. However, the relationship between hyperglycemia and OS is inconsistent in diabetic clinical studies. The aim of this study was to evaluate the effect of normalization of blood glucose levels on urinary 8-epi-prostaglandin F(2alpha) (8-epi-PGF(2alpha)) excretion at the onset of type 1 diabetes. We studied 14 type 1 diabetic patients (50% males; mean age, 24.3 +/- 4.9 years) and 14 control subjects matched by age and body mass index. A 24-hour urine collection was performed to determine 8-epi-PGF(2alpha) as an integrated index of OS production at baseline, before starting insulin therapy, and 16 weeks later. Insulin treatment induced a significant reduction in glycosylated hemoglobin (HbA(1c)) (from 11.5% to 5.4% P =.0001), triglycerides (from 1.0 to 0.8 mmol/L, P =.002), and an increase in high-density lipoprotein (HDL)-cholesterol levels (from 1.1 to 1.5 nmol/L, P =.01) at week 16. This improvement in metabolic control was associated with a statistically significant reduction in 8-epi-PGF(2alpha) values (from 92.0 +/- 41.5 to 66.9 +/- 28.9 pg/mg urinary reatinine excretion, P =.015), although compared with the control group, 8-epi-PGF(2alpha) values remained higher in diabetic patients (66.9 +/- 28.9 v 39.1 +/- 13.8 pg/mg creatinine, P =.004). Enhanced OS is present in early clinical phases of type 1 diabetes, and the amelioration in metabolic control is associated with improvement in this pathogenic pathway.     

可溶性血管细胞黏附分子1在肺结核发病机制中的作用和临床意义

目的探讨可溶性血管细胞黏附分子1(sVCAM-1)在肺结核发病机制中的作用和临床意义,及其与肿瘤坏死因子α(TNF-α)和γ干扰素(IFN-γ)的关系。方法采用酶联免疫吸附测定(ELISA)法检测未经治疗的35例肺结核患者(肺结核组)、20名健康人(对照组)血清 sVCAM-1、IFN-γ水平,放射免疫分析(RIA)法测定血清 TNF-γ水平。肺结核组中,血型播散性肺结核(Ⅱ型)15例,继发性肺结核(Ⅲ型)20例,后者于治疗2个月后再次采血。结果肺结核组血清 sVCAM-1、TNF-γ和 IFN-γ的水平分别为(822±206)、(1.5±1.1)和(23±13)μg/L,高于对照组(428±73)、(0.2±0.1)和(16±10)μg/L,差异有统计学意义(P 值分别<0.01、<0.01、<0.05);血型播散性肺结核(Ⅱ型)患者的血清 sVCAM-1和 TNF-α的水平分别为(897±144)、(2.0±1.4)μg/L,高于继发性肺结核(Ⅲ型)患者的(765±230)和(1.2±0.6)μg/L,差异有统计学意义(P 值均<0.05);IFN-γ在Ⅱ型与Ⅲ型肺结核患者之间差异无统计学意义(P=0.222)。抗结核治疗后,血清 sVCAM-1和TNF-α水平分别为(532±103)、(0.8±0.8)μg/L,与治疗前相比差异有统计学意义(P 值均<0.01);治疗2个月后 sVCAM-1和 TNF-α水平仍高于对照组(P<0.01);IFN-γ治疗后水平高于治疗前(P<0.05)。肺结核治疗前血清 sVCAM-1与 TNF-α、IFN-γ均呈正相关(r 值分别为0.669、0.560,P 值均<0.01)。对照组和肺结核组治疗后血清 sVCAM-1与 TNF-α、IFN-γ之间均无相关性。结论sVCAM-1可以作为判断病情严重程度和评价疗效的一项临床指标。